Abstract

Background and Purpose—Thrombolysis for acute ischemic stroke in the elderly population is seldom administered.

Methods—In this study, we evaluated the risks of thrombolysis, including the mortality and intracerebral hemorrhage (ICH) rates in this population. A cohort of patients was identified from the National Inpatient Sample database for the years 2000–2006. Age was categorized in 2 groups, including those between 18 and 80 years and those >80 years. Multivariate logistic regression analysis was used to assess covariates associated with hospital mortality and ICH. A total of 524 997 patients were admitted for acute ischemic stroke; 143 093 (27.2%) were >80 years. A total of 7950 patients were treated with thrombolysis, of which 1659 (20.9%) were >80 years. Elderly patients received less frequent thrombolysis compared with the younger population (1.05% versus 1.72%).

Results—In the whole cohort, the mortality rate was higher in the older population (12.80% versus 8.99%). For those treated with thrombolysis, the mortality rate and risk of ICH were higher among those >80 years (16.9% versus 11.5%; odds ratio: 1.56 [95% CI: 1.35 to 1.82] and 5.73% versus 4.40%; odds ratio: 1.31 [95% CI: 1.03 to 1.67], respectively). Multivariate logistic regression analysis showed that the presence of ICH (odds ratio: 2.24 [95% CI: 1.89 to 2.65]) was associated with higher mortality rates but not the use of thrombolysis (odds ratio: 1.14 [95% CI: 0.98 to 1.33]).

Conclusions—Despite the higher mortality rate in the older population, the use of thrombolysis does not predict death; however, the use of thrombolysis was associated with high risk of ICH.

Advanced age is a recognized risk factor for acute ischemic stroke (AIS), and the incidence of stroke increases with age.1–3 Near half of all strokes occur in people who are aged >70 years, and nearly a quarter occur in patients who are >85 years of age.4,5 The Oxford Vascular Study indicated a 12-fold increase in the incidence of AIS in the age group >85 years compared with the younger population.6 Similarly, a third of the Canadian stroke population was above the age of 80 years, as attested by the Canadian Stroke Network.7 Stroke in the elderly is of serious concern not only because of the higher incidence but also because of the increased disability associated with it.2,8 Therefore, the elderly demographic remains important to evaluate, especially in the presence of various preventative and therapeutic interventions. Despite the fact that the current guideline does not characterize age as exclusion,9 the use of thrombolysis for AIS in elderly has been a debatable subject. This is mainly because most of the pioneering randomized trials, including the National Institute of Neurological Disorders and Stroke, had excluded elderly patients.10–14 In addition, elderly patients are at a known high risk of intracerebral hemorrhage (ICH).15 For these reasons, thrombolysis is a less used therapy in the elderly population, where disease incidence is the highest. With the available guidelines and the increasing physicians comfort with thrombolysis, we hypothesized an increasing use of this intervention in the elderly in different US hospitals.

We aimed to identify the hospital mortality and ICH rates associated with the thrombolysis therapy for AIS in the elderly population. We also attempted to identify the trends of hospital use of thrombolysis therapy in elderly patients, which may reflect physician’s learning curve and comfort in treating elderly population with AIS.

Methods

National Inpatient Sample (NIS) is administrative database that represent a 20% stratified sample of inpatient admissions from 1000 acute care US hospitals maintained by the Agency for Healthcare Quality and Research. Information on diagnoses and procedures was identified using the International Classification of Disease, 9th Revision, Clinical Modification (ICD-9-CM) codes for diagnoses and procedures. We identified admissions for AIS in the NIS database from 2000 through 2006 by searching the ICD-9-CM using the diagnostic clinical classification software codes 109 (acute cerebrovascular accident) and 110 (precerebral artery occlusion), with or without infarction as the primary diagnosis.16 These codes have a sensitivity of 84% in identifying hospitalizations for AIS.17 Only patients with emergent admission type were included in this analysis. Exclusion criteria also included age <18 years, patients with sickle cell disease, central nervous system infections, trauma, poisoning by external substances, alcohol withdrawal, congenital central nervous system anomaly, hypoglycemia, and anoxic brain injury. We excluded transfers to another hospital because patients might be represented in the same data set twice. This study was deemed exempt by the University Hospitals Case Medical Center Institutional Review Board, because NIS is a public database with no personal identifying information.

Data Cleansing

Missing observations on the death status (n=2116; 0.4%) and observations on missing age (n=65) were eliminated from the total sample. The most common variable with missing data was race (24.8%), which was classified in 4 categories (white, black, Hispanic, and others). A similar proportion of missing race data in the NIS database because of state suppression of this variable was present in previous NIS analysis.16 Because of the multiple categories, we did not impute the race variable. The socioeconomic status was approximated by the income-associated zip code. Data with hospital charge less than $100 was likely a mistake and coded missing if found. Because of a capped length of stay implemented in 1992, data with length of stay exceeding 365 days were eliminated.

Statistical Analysis

Student t test and Wilcoxon rank-sum tests were used to compare the mean and median of continuous variables. χ2 test or Fisher exact test was used to compare proportion between categories. Age was categorized in 2 groups, including those between 18 and 80 years and those >80 years. For univariate analysis, we used Cochran-Mantel-Haenszel test. A multivariate stepwise logistic regression model fitted to determine the independent association of significant variables for the outcomes of in-hospital mortality and ICH. For the first model (outcome of hospital mortality), the following covariates were used: the basic demographics of age category, sex, race, and socioeconomic status; hospital-associated complications (ICH, endotracheal intubation, gastrointestinal bleedings, and sepsis); and comorbidity index. The same covariates except for ICH were used for the second model (outcome of ICH). The significance level was set a priori at P<0.001. We used the Cochran-Armitage test for linear trend of a discrete variable; thrombolysis administered in elderly for each year included in this study divided by the number of stroke admissions as a denominator, that is, the ratio of thrombolysis to stroke admissions per year. This analysis was stratified by hospital characteristics, including hospital teaching status (teaching versus nonteaching) and hospital location (urban versus rural). A trend was considered significant at P<0.05. All of the statistical tests were performed using the SAS 9.2 (SAS Institute).

Results

In this analysis, 524 997 patients were among the initial cohort of those admitted with AIS, and 30% of those (n=158 580) were >80 years (Supplemental Table I, available at http://hyper.ahajournals.org). Among all of the patients, the mean age was 71.2 years; and among the elderly population, the mean age was 86.2 years. The proportion of women (66.8% versus 48.9%) and whites (62.4% versus 50.0%) was higher among the elderly patients compared with the younger population. As expected, the third-party payer was the Medicare for the elderly population (92.8% versus 56.7%). Charlson comorbidity index, the length of hospital stay, and total hospital charges were essentially similar in both groups. However, more patients among the younger population had respiratory failure needing endotracheal intubation (7.38% versus 4.23%; P<0.0001). The overall mortality rate in this cohort was 10.1% and was higher in the elderly population (12.8% versus 9.0%; P<0.0001).

Among those patients treated with thrombolysis for AIS (Table 1), similar patterns of the basic demographics were noticed compared with the parent cohort, including sex, race, primary payer, and the comorbidity indices being mild in the majority of the cohort. However, those treated with thrombolysis had a longer hospital stay (by ≈1 day) and a double hospital charge ($33 592 compared with the parent cohort $16 582). Neither the length of hospital stay nor the hospital charges was higher in the elderly population treated with thrombolysis compared with the younger population. In the original cohort, more patients were discharged home than to rehabilitation centers if they were young (51.7% versus 35.2%), whereas more patients were discharged to rehabilitation centers than home in the elderly sample (54.9% versus 30.1%; Figure 1). The treated populations in both groups were likely to be discharged to a rehabilitation facility (60.7% in the elderly and 45.9% in the younger population) and less likely to be discharged home (19.1% in the elderly and 37.3% in the younger population) compared with the parent cohort. Bivariate analysis of hospital mortality and treatment-associated complications in the treated population are shown in Table 2. Among the elderly population treated with thrombolysis, the risk of death is higher (16.9% versus 11.4%; odds ratio [OR]: 1.56 [95% CI: 1.35 to 1.82]). A slight increase in the hemorrhage rate was also noted in the elderly population (5.73% versus 4.4%; OR: 1.31 [95% CI: 1.03 to 1.67]). The risk of endotracheal intubation was lower in the elderly population (8.38% versus 12.56%; OR: 0.63 [95% CI: 0.52 to 0.76]). Among those treated with thrombolysis, bivariate analysis showed increased risks of death and ICH among the treated elderly population. Multivariate logistic regression analyses (Table 3) for an outcome of death in the elderly population treated with thrombolysis showed a higher risk of death among white compared with black subjects (OR: 1.56 [95% CI: 1.38 to 1.75]) and in the presence of the following complications: ICH (OR: 1.95 [95% CI: 1.49 to 2.54]), endotracheal intubation (OR: 17.24 [95% CI: 15.79 to 18.82]), and gastrointestinal hemorrhage (OR: 2.1 [95% CI: 1.76 to 2.50]). Elderly patients with severe comorbidity index are also at a higher risk of death compared with those with milder comorbidities (OR: 1.53 [95% CI: 1.25 to 1.89]). The use of thrombolysis in the elderly was not a predictor of death (OR: 1.22 [95% CI: 0.93 to 1.89]; P=0.13) but was associated with increased risk of ICH (OR: 9.69 [95% CI: 3.50 to 6.17]).

Table 2. Bivariate Analysis for Outcomes in Elderly Patients Treated With Thrombolysis Compared With Those <80 Years (Treated With Thrombolysis) and Compared With the Older Population (Untreated With Thrombolysis)

Figure 1. Discharge disposition of the total cohort and those treated with thrombolysis stratified by age.

Trend analysis of US hospital use of thrombolysis therapy in the elderly population was shown in Supplemental Table II and Figure 2. Among all of the elderly admissions, the trend analysis showed an increase in the rates of treatment over time, being the lowest given in year 2000 (0.63%) and highest rates given in the years 2005 and 2006 (1.28%). When stratified by certain hospital characteristics, the rates of thrombolysis were the highest in teaching hospitals and the lowest in rural hospitals (Figure 2). A trend toward increase in thrombolysis use in teaching hospitals has steadily increased from 0.77% in year 2000 to 2.87% in year 2006 (P<0.0001). In nonteaching hospitals, the rates of thrombolysis remained unchanged during the years 2000 through 2004 (P=0.49), although, these rates picked up to 0.94% in the year 2005 and reached 1.18% in year 2006. The rates of thrombolysis in rural US hospitals remained unchanged during the years included in this study (P=0.96).

Figure 2. Trend of US hospital use of thrombolysis in elderly population.

Discussion

In agreement with previous reports,16,19,20 we found very low rates of thrombolysis in the total cohort (1.51%), and the rates further decreased among the elderly population (1.05%). Those treated with thrombolysis (old or young) were likely to have a longer hospital stay and higher hospital charges in both age groups. The longer hospital stay in the treated population does not necessarily reflect a worse outcome. Treated populations in both age categories are likely to have a worse stroke severity, and they are subject to few complications, including ICH,21 and, hence, they had a longer hospital stay. In contrast with a single center Danish study, Sølling et al22 showed a decreased length of hospital stay in stroke as well as nonstroke populations during the recent era of thrombolysis compared with a historic control. We found a high mortality associated with thrombolysis in both age categories; therefore, a multivariate analysis failed to show association between mortality and the age category. A smaller observational study of 181 patients (56 of which were >80 years) showed higher hospital mortality rate, approaching 20% in the elderly compared with 11% in the younger population.23 A high mortality rate was similarly observed in a small randomized trial comparing the same age categories.24 The same trial failed to show any favorable functional outcome, as measured by modified Rankin Scale in elderly patients treated with thrombolysis.24 Three-month mortality was even higher in an Italian study, reaching 34% in the elderly population.25 The aforementioned studies were all small, and conclusion could not be confidently derived.

Our study also confirms that patients who received thrombolysis for AIS had increased risk of ICH, which, in turn, predicted the hospital mortality. The risk of ICH in our study was similar to those reported in large series,16,20 and slightly lower than those reported by the National Institute of Neurological Disorders and Stroke Trial.21 Chen et al23 and Pundik et al26 reported a higher risk of symptomatic ICH in treated elderly cohorts compared with the younger population (7.1% versus 6.3%; 12.8% versus 10.4%); however, both of these differences were not statistically significant. In contrast to these studies, including ours, symptomatic ICH was higher in the younger population (6% versus 3%), as reported by Tanne et al24 Although the association between thrombolysis and ICH was debated in the past,14 the risk of ICH in the elderly remains a valid concern if thrombolysis is considered for treatment of AIS. Interestingly, we found a higher frequency of respiratory failure needing endotracheal intubation in the younger population despite the lower mortality rate in this group. A plausible explanation for this observation may be the conservative physician’s attitude toward the elderly population and/or the likelihood of revealed advanced directives in this population (eg, do-not-resuscitate orders), to avoid invasive therapies, such as endotracheal intubation.

Despite the controversial aspects of thrombolysis in the elderly, we found a trend of increasing hospital use of thrombolysis over the recent years. Teaching hospitals in urban communities expectedly treated more patients with thrombolysis; this is in part because some of these hospitals are tertiary care centers, where most referrals occur. Many studies had observed similar increase in the rates of thrombolysis for AIS in US hospitals.27–29 As mentioned, the rates for the administering thrombolysis in different studies, including ours, are very low. A recent study by Kleindorfer et al28 showed that two thirds of US hospitals did not administer thrombolysis for AIS, most of which are located in less populated geographical area, such as the South and Midwest regions of the United States. Furthermore, there is an increase in thrombolysis use across different hospital types but not in hospitals located in rural areas. Lack of public education about AIS symptoms, in-hospital delays, and lack of specialized physician and resources is among the multiple reasons for the low rate of thrombolysis.30,31 These problems are even more prominent in rural areas where health care is provided by smaller community hospitals. Other than education and access to specialized units, telemedicine technology may assist in solving some of the logistical issues in remote hospitals.19,32

There are limitations in this study worth mentioning; first, the NIS database lacks specific details on the dose, the route of administration (intravenous versus intra-arterial) of the thrombolytic agent, as well as the time data, that is, onset to treatment. The risk of ICH may increase with protocol violation, information lacking in the NIS database.20 In addition, the NIS data set lacks information about stroke-specific features, such as stroke severity scale, anatomic location, 3-month mortality rate, and whether those patients were treated with other therapeutic agents that alter outcomes. Similarly, ICD codes would not identify symptomatic from nonsymptomatic ICH. Lastly, this study is observational, and selection bias is a possibility. Regardless, a large randomized, clinical trial to assess the efficacy and safety of thrombolysis for this demographic will be practical. A trial may specifically address the safest dose and type of thrombolytic agent to be used for the elderly population, as well as age-related comorbidities, such as baseline neurological function and the presence of dementia. Although thrombolysis for AIS in the elderly population is not prohibited, physicians must be cautious for the potential complications, including ICH.

Acknowledgments

Disclosures

None.

Footnotes

The online-only Data Supplement is available at http://stroke.ahajournals.org/cgi/content/full/STROKEAHA.110.588632/DC1.